Is MSH3 p.Ala145Pro (c.433G>C) pathogenic?

MSH3 p.Ala145Pro (c.433G>C) is classified Uncertain significance in MSH3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-29). AlphaMissense: likely benign (0.0838); Very rare (popmax 0.000169%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with MSH3 p.Ala145Pro (c.433G>C)?

MSH3 p.Ala145Pro (c.433G>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MSH3 p.Ala145Pro (c.433G>C) in the general population?

MSH3 p.Ala145Pro (c.433G>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about MSH3 p.Ala145Pro (c.433G>C)?

AlphaMissense predicts likely benign (score 0.0838) — an in-silico prediction, not a clinical call.

MSH3 p.Ala145Pro

c.433G>C · rs1580546606 · VCV1483367

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0838 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0838	likely benign
REVEL	0.328	indeterminate
SaProt	LLR -5.86	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.7	GERP 2, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 221 kb · p 0.0024 · regional, not allelic
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,992 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,790 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MSH3
Protein: p.Ala145Pro
Coding: c.433G>C
MANE Select: NM_002439
dbSNP: rs1580546606
Type: single nucleotide variant
Location: chr5:80665217 (GRCh38)
Gene constraint: LOEUF 1.027 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.48 · 25 PDB
Residue 145: the 'interaction with exo1' region

Full MSH3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MSH3 p.Ala145Ser Uncertain significance ★★ ⚠ same residue
MSH3 p.Ala145Val Uncertain significance ★★ ⚠ same residue
MSH3 p.Ala145Thr Uncertain significance ★ ⚠ same residue
MSH3 p.Ala145= Likely benign ★ same residue
MSH3 c.1341-2A>C Likely pathogenic ★★ same condition
MSH3 c.1341-2A>G Likely pathogenic ★★ same condition
MSH3 c.1568+1G>C Likely pathogenic ★★ same condition
MSH3 c.1653+1G>A Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/msh3-p-ala145pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown